Full Text PA-95-005

AIDS, DRUG ABUSE AND NEUROBIOLOGY

NIH GUIDE, Volume 23, Number 40, November 18, 1994

PA NUMBER:  PA-95-005

P.T. 34

Keywords: 
  Drugs/Drug Abuse 
  AIDS 
  Neurological Disorders 
  Biology, Molecular 


National Institute on Drug Abuse

PURPOSE

The Acquired Immunodeficiency Syndrome (AIDS) is particularly
prominent in populations of drug abusers.  The onset and spread of
HIV infection and the development of AIDS in this population is only
superficially understood.  Associated with the AIDS epidemic is the
re-emergence of tuberculosis (TB) and other diseases not early
recognized as associated with AIDS.  The reduction in the immunologic
competence of the abuser by various drugs may be important in the
selection and progression of particular diseases.  Also, many drugs
of abuse are themselves neurotoxic and may initiate or enhance the
development of dementia relative to HIV and otherwise compromise the
central nervous system.  To enhance knowledge regarding drug
modulation of the HIV infectivity and progression to AIDS,
neuroscientists, endocrinologists, immunologists, chemists, molecular
biologists and others are collectively invited to submit research and
conference grant applications (singly or jointly) to bring about an
understanding of how drug abuse affects HIV-related disease states.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This program
announcement, AIDS, Drug Abuse, and Neurobiology, is related to the
priority area of alcohol and other drugs.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0, or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and
non-profit, public and private organizations, such as colleges,
universities, hospitals, laboratories, units of State and local
government, and eligible agencies of the Federal government.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards and program project (P01) grants.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISMS OF SUPPORT

Support mechanisms include regular individual research project grants
(R01), small grants (R03), conference grants (R13), FIRST awards
(R29), Interactive Research Project Grants (IRPGs), and program
projects (P01).

Because the nature and scope of the research proposed in response to
this program announcement may vary, it is likely that the size of an
award will vary also.

RESEARCH OBJECTIVES

NIDA has comprehensive neuroscience and immunological research
programs.  This program announcement focusses on the interactions of
these two broad areas and related problems of HIV infectivity,
especially in the central nervous system (CNS), and complements other
NIDA program announcements concerning drug abuse and AIDS.

Basic Immunologic Research:  Research covered in NIDA's previous AIDS
announcement still of interest include:  (a) basic understanding of
direct and indirect drug actions on immune cells, including studies
of unique drug receptors, (b) drug modulation of viral replication
and ontogeny within the host and host cells, and (c) appropriate
animal studies designed to understand disease onset and progression.

Redefined and broadened areas of research are outlined below:

AIDS Neurologic Manifestations:  AIDS is frequently accompanied by
neural degeneration that results in progressive cognitive, behavioral
and motor deficits (known as the AIDS Dementia Complex (ADC)).
Investigations focussed on understanding the disease have made
several important findings.  For example, it has been shown that the
HIV coat protein modulates the NMDA (N-methyl-d-aspartate) type of
excitatory amino acid receptor and psychomotor stimulants act on this
receptor.  This suggests that there might be important mechanisms in
common between AIDS- and drug (of abuse) -induced neural damage. If
this is the case, then there also may be common approaches to prevent
or treat the neurotoxic process.  Potential research areas include:

o  Mechanism of action of drugs of abuse (e.g., psychomotor
stimulants, "designer drugs") on the progression of ADC using in
vitro and in vivo models.

o  Nature of viral damage to specific functional  brain regions or
circuits especially relevant to drug abuse (e.g., mesocortical limbic
system, hippocampus, cortical association areas, pyramidal and
extrapyramidal motor areas, etc).

o  Mechanism of drug modified glutamate-induced neurotoxicity and
AIDS-dementia-complex utilizing SAR approaches (e.g., study of NMDA
antagonists, PCP, MK-801, and memantine); this includes the synthesis
of new compounds.

o  Drug (of abuse) modulation of induction, propagation (e.g., across
the blood-brain-barrier) and mechanism of drug modulation of HIV
action (e.g, gp120 protein) in microglia (e.g., via cytokines) and
their effects on neural cells.

o  Interrelationships of various drugs of abuse with non-neural cells
(e.g., glia) to determine the basis for the onset and progression of
specific complications, i.e., Kaposi's sarcoma, opportunistic
infections, neurodegeneration.

o  Mechanism of neural degenerative diseases and other glial
modulated changes exerted by release of cytokines; especially where
opiates and other abused drugs may impact.

o  Multiple actions of drug (e.g., marijuana) use by AIDS patients in
immune suppression and/or neurotoxic action, which may enhance the
neurotoxicity of HIV.

Neuronal Interactions with Other Systems (HPA, THYMUS):  The
transmission/progression of HIV is not only inhibited by the immune
system, but also is dependent on several interacting systems
primarily under CNS control.  Mechanistic studies are needed to
elucidate the mechanism of how drug-induced modulation of CNS control
of susceptibility, disease onset and morbidity occurs, i.e., through
direct action on the immune system, or indirectly via the
neuroendocrine system (e.g., through interleukin release from the CNS
or the hypothalamic-pituitary-adrenal axis (HPA) resulting in
stimulation/depression of macrophages, lymphocytes).  As opiates and
other drugs inhibit neural and peripheral systems, studies should
focus on understanding the mechanisms of such action on the onset
and/or progression of the AIDS syndrome.  Areas of research interest
involve, but are not restricted to, studies of:

o  Central system's and corresponding peripheral receptors (e.g., in
lymph, adrenals, pituitary) pertinent to these actions.

o  Nature and mechanisms of the inhibition of immunity by drugs of
abuse, including accessory cell function with a focus on receptors on
these peripheral cells.

o  Key role of interleukins (e.g., IL1, TNFa), other transmitters
(e.g., NO) as primary intermediates involved in abused drug actions
on the immune and nervous systems.

o  Significance and mechanism of opioid suppression of the immune
system for pain therapy in AIDS patients; examine the potential of
alternative analgesics (including acupuncture) which do not affect
the immune system.

The nervous system is linked to the immune system through
noradrenergic, dopaminergic and peptidergic fibers innervating
endocrine tissue via common chemical messengers and receptors.  For
example, interlukins inhibit the HPA-induced release of
corticosterone, an action modulated by opioids through the central
serotonergic system.  Also, hypothalamic cytokine receptor(s) similar
to lymphocytic receptors appear to mediate ACTH (and
opiomelanocortin) secretion in response to IL1 via CRF activation.
Other areas of investigation include:

o  Opioids (exogenous as well as endogenous) indirect actions on
immunity as modulated by the neuroendocrine system.

o  Alteration by drugs of abuse on the feedback responses between the
endocrine or immune systems and the CNS.

o  Role of stress in these actions.

Several opioid systems have been identified in the immune cells.  Of
these the "Enkephalin-type" systems of lymphocytes have been
identified as key intermediaries in their ability to kill viruses and
modulate rejection during organ transplantation.  Studies might
examine:

o  Relationship and mechanism of immunomodulation by "enkephalin" and
other systems of lymphocytes.

o  Synthesis of new delta antagonists/agonists to understand the
mechanisms of, or to improve, their anti-viral action.

Perinatal Issues:  Abuse of illicit drugs during pregnancy impacts on
the mother's health and the neural development of her fetus. The
consequences of maternal substance abuse on the developing CNS,
neuroendocrine and immune systems, pediatric HIV infection and
infant's increased susceptibility to infections are important issues
to be addressed and may include:

o  Effects of abused drugs on the mode of transmission of HIV prior
to, during birth, or postnatally.

o  Role and status of these drugs on maternally-derived antibodies
and other immune protection for the newborn.

o  In rodents and other animals, critical periods of development when
drug activation of the immune system by viral antigens or certain
cytokines profoundly affects the HPA.

o  Studies of the placenta, which has both neuroendocrine and immune
functions, are important for understanding the development of the
fetus, and could shed some light on the impact of drugs of abuse on
the neonatal development, such as:

o  Abused drugs alteration of the distribution of neuropeptides,
immune cell surface markers, cytokines, growth factors and receptors
in normal human and animal (primate) placentas.

Other Studies:  Health seems to decline more rapidly and more
severely in HIV-infected drug abusers than in other HIV subjects.
Recent research has shown that morphine treatment (in monkeys) leads
to the development of a new strain of HIV that is less responsive to
treatment.  This mutability has also been demonstrated in human
populations.  Studies might include:

o  Interaction of drugs of abuse with the HIV and the disease process
related to mutant HIV strains.

o  HIV treatment drugs in appropriate model systems, their effect on
immune capacity of drug abusers, especially for methadone and other
drug treatment subjects.

The pharmacokinetic parameters (absorption, distribution, metabolism
and elimination) of drugs, virus and immune components transported
across the blood-brain-barrier and placental barrier are important to
understanding the onset and progression of HIV and the treatment of
AIDS.  Studies in this area may shed light on viral transmission to
the CNS and to the fetus, including:

o  Drugs of abuse on the production of peptides (e.g., cytokines),
other constituents and transport across these barriers.

o  Drugs (e.g., cocaine) influence on the transport, metabolism of
AIDS treatment drugs (e.g., AZT)

Behavior Studies:  Behavioral approaches to study drug abuse and AIDS
could range from preclinical studies such as the development of
animal models to examine AIDS-related behaviors to the more clinical
oriented formation and/or improvement of behavior modification
techniques.  Research issues might include:

o  Neural basis for risk taking:  behavioral, neurobiologic, and
cognitive mechanisms negatively predicting making decisions, e.g.,
trying cocaine, using unsterilized needles, having unprotected sex,
other risks; single or multiple factor mechanisms related to
inappropriate risks; gender factors.

o  Interventions for risk taking:  e.g., apply attention deficit
therapies (behavioral and pharmacological) to risk taking.

o  Influence of drugs of abuse on risk-taking behavior: e.g., measure
if abused drugs, like alcohol, increase risk taking and impair
judgment at doses much lower than those that affect coordination and
speech.

o  Behavior modification techniques to reduce the liability of
contracting AIDS, especially through drug self-administration.

o  Negative and positive reinforcement approaches to control this
risk taking.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the standard AIDS-related
application deadlines as indicated in the application kit.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301-435-0714.  The title and number of this program announcement must
be typed in Item 2a on the face page of the application.

FIRST applications must include at least three sealed letters of
reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

The completed original application and five legible copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

The National Institute of Mental Health (NIMH) supports research
directed at understanding the impact of HIV infection on the central
nervous system, as well as research to develop effective strategies
to prevent or reduce high risk behaviors that place individuals at
risk for HIV infection.  The NIMH is interested in receiving
applications independent of this program announcement, which address
these issues.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by an initial review group in accordance with the
standard NIH peer review procedures.  Following scientific-technical
review, the applications will receive a second-level review by the
appropriate national advisory council.  Small grant (R03)
applications do not receive a second level review by NIH staff.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the
announcement.  Applications judged to be competitive will be
discussed and be assigned a priority score.  Applications determined
to be non-competitive will be withdrawn from further consideration
and the Principal Investigator and the official signing for the
applicant organization will be notified.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  conformance with the NIH Guidelines for the Inclusion of Women and
Minorities as Subjects in Clinical Research.

The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications recommended for further consideration assigned to the
Institute.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, program balance among research areas of the announcement, and
availability of funds.

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or to answer questions from potential applicants
is welcome.

Direct inquiries regarding programmatic issues to:

Charles W. Sharp, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-31
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-1887
Email:  csharp@aoada.ssw.dhhs.gov

Direct inquiries regarding fiscal or grants management issues to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
Parklawn Building, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  gfleming@aoada.ssw.dhhs.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.279.  Awards are made under authorization of
Section 301 of the Public Health Service Act (42 USC 241) and
administered under PHS policies and Federal Regulations of Title 42
CFR 52, "Grants for Research Projects," Title 45 CFR Part 74 and 92,
"Administration of Grants," and 45 CFR Part 46, "Protection of Human
Subjects."  Title 42 CFR Part 2, "Confidentiality of Alcohol and Drug
Abuse Patient Records," may be applicable to these awards.  Title 42
Part 241(d), "Certificates of Confidentiality and Communicable
Disease Reporting," will also apply.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

Sections of the Code of Federal Regulations are available in booklet
form from the U.S. Government Printing Office.

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.

.

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